Prostaglandin (to be referred to as PG hereinafter)s are compounds which show strong activities with a very small amount by broadly distributing in various organs and body fluid in the living body and have a great variety of physiological activities such as relaxation and contraction of smooth muscle, contraction and dilation of blood vessel, platelet agglutination inhibitory activity and the like. Among PGs, since PGE2 has physiological activities such as cell protective activity, uterine contraction, pain producing activity, acceleration of digestive tract peristalsis, awakening activity, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity, and it has been used in the prevention and treatment of various diseases.
However, since PGs are chemically very unstable, their effective administration methods are limited to intravenous administration and the like and have a possibility of side effects such as expressing hypotension, gastroenteric disorder, skin blood vessel edema (The Journal of Clinical Investigation, vol. 108, pp. 25-30, 2001). 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-5-oxocyclopentyl)ethyl]sulfanyl} butanoic acid is a compound known as 5-thia-ω-substituted phenyl-prostaglandin E derivative having agonistic activity for EP4 which is one of PGE2 receptor subtypes. It is useful for preventing and/or treating various diseases such as bone disease and the like (e.g., see Patent References 4 and 5). Not only the compound but also C1-4 alcohol ester of 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoic acid is a very unstable compound. It is known that they change over time easily by the influences of heat, moisture, and the pH, etc. It is considered that when systemic administration such as oral administration or intravenous administration (e.g., rapid intravenous injection, intravenous drip infusion or the like) of the C1-4 alcohol ester is performed, the C1-4 alcohol ester is converted into an active form, and if the blood concentration of the active form rapidly increases, an influence on the cardiovascular system such as hypotension or an increase in heart rate or a side effect such as diarrhea or cutaneous angioedema may be caused. Further, in the case where a bone disease is treated, since bone formation takes a long time, it is necessary to administer a drug many times through intravenous administration and a burden is imposed on a patient, therefore, it is not necessarily satisfactory.
In view of this, novel administration route and dosage form of PGs have been studied. With regard to the novel administration route and dosage form of PGs for applying them to a bone disease, it has heretofore been known that the C1-4 alcohol ester can be used for preventing and/or treating bone loss disease by formulating it into a controlled release preparation (e.g., a microcapsule preparation, a microsphere preparation, a nanosphere preparation or the like) for local administration, or by dissolving it in an organic solvent along with a bioabsorbable polymer followed by lyophilization thereby to prepare an implantable sustained release film preparation for local administration (e.g., see Patent references 6 and 7). Further, it is disclosed that an EPI agonist which is one of the PGE2 receptor subtypes is percutaneously administered for increasing bone volume (e.g., see Patent reference 8). Further, it is disclosed that local administration of an EP4 receptor selective agonist is useful for the treatment of bone diseases (e.g., see Patent reference 9).
Further, as one of the novel dosage forms, a possibility of a percutaneous absorption preparation such as an adhesive preparation has also been studied (e.g., see Patent references 1, 2 and 3).
As for a characteristic of such an adhesive preparation, there is an advantage in that a burden to patients is reduced, for example, treatment can be performed at home, drug administration is not painful, the adhesive preparation can be removed easily after completion of medication, etc. However, due to the barrier function of the skin, percutaneous absorption of a drug is generally poor and it is often difficult to deliver a drug in an amount necessary for exhibiting the drug effect through the skin with a practical and limited applied area. Also, the adhesive preparation has many problems such as drug stability, sustainability, effect, safety (occurrence of side effects) and skin irritation (e.g., erythema, edema, itching, rash, pigmentation or the like). Many studies have been made for avoiding various problems of concern for such an adhesive preparation.
For example, it is known that depending on the compatibility of an additive (an amphiphilic solubilizer, a percutaneous absorption accelerator, a dermatological side effect relieving agent, a drug stabilizer and/or a crosslinking agent, or the like) or a filler to be incorporated in the adhesive preparation, the controlled release or acceleration of permeation of an active ingredient is adjusted, and the stability, percutaneous absorption or the like of a drug is improved.
As one example, Japanese patent No. 2655983 discloses a method of producing a percutaneous preparation with a matrix type structure or a storage tank type structure containing a main content layer obtained by mixing a drug mixture with a hydrophobic adhesive as a method of improving the stability of a drug having a tyrosinase inhibitory activity. It is described that the main content layer is a mixture of a hydrophobic adhesive, a percutaneous absorption accelerator for a drug, a drug stabilizer, a solubilizer for a drug in a system, and a dermatological side effect relieving agent (see Patent reference 10).
Further, it is disclosed that a percutaneous absorption preparation comprising a backing layer and an adhesive layer containing a drug, wherein the adhesive layer contains a mixed adhesive base having a hydrocarbon rubber and a silicon-containing polymer is excellent in percutaneous absorption of the drug in the preparation, and has low skin irritation and high stability of the drug over time (see Patent reference 11).
JP-A-5-238929 discloses a long-term sustained release preparation characterized in that a therapeutic agent for a metabolic bone disease is contained in silicone, and discloses that a substance for controlling the release rate of albumin or the like is used for controlling the release rate of a drug (see Patent reference 12).
When a plurality of additives are added thereto, the drug stability, percutaneous absorption and the like are improved, however, there is a concern that skin irritation or the like may be caused by the influence of the additives.
Further, as for 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-5-oxocyclopentyl)ethyl]sulfanyl} butanoic acid, a percutaneous absorption preparation for controlling blood concentration containing an ester thereof and a base for external preparations is disclosed. As the base for external preparations here, bases such as a styrene-isoprene-styrene block copolymer, an acrylate resin, and an acrylic copolymer resin are described (see Patent reference 13).
However, it was found that the percutaneous absorption preparation has a problem in the stability over time. That is, the drug is degraded while the preparation is being stored, therefore, there is a concern that a sufficient drug effect cannot be exhibited when it is used.
Further, in the case where a C1-4 alcohol ester of 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoic acid is used for a bone disease, particularly for bone fracture, since an affected area is immobilized in a cast, a drug cannot be applied to the affected area in some cases. Further, when an adhesive preparation is continue to be applied to the same area, itching or rash is caused in some cases. Moreover, depending on individual difference, difference in application site or the like, the drug concentration in the body becomes unstable. Therefore, there is a concern that, for example, the blood drug concentration rapidly increases and a very potent effect is exhibited or a side effect is exhibited. In order to avoid such a problem, an adhesive preparation which is not necessarily required to be applied to an affected area and is capable of exhibiting the same drug effect wherever in the body it is applied has been demanded. In order to achieve such a demand, an adhesive preparation with a small variation in drug skin permeability due to difference in application site, individual difference, the presence or absence of skin lesion such as injury or skin inflammation, etc., that is, an adhesive preparation with a small change in skin permeability is useful.
[Patent Reference 1] JP-A-58-134019
[Patent Reference 2] JP-B-07-25666
[Patent Reference 3] Japanese Patent No. 2910857
[Patent Reference 4] International Publication No. 00/003980
[Patent Reference 5] International Publication No. 01/037877
[Patent Reference 6] International Publication No. 03/009872
[Patent Reference 7] International Publication No. 03/041717
[Patent Reference 8] International Publication No. 00/051585
[Patent Reference 9] JP-A-2001-181210
[Patent Reference 10] Japanese Patent No. 2655983
[Patent Reference 11] JP-A-2006-16382
[Patent Reference 12] JP-A-05-238929
[Patent Reference 13] International Publication No. 06/118173